The applicant has a funded research program in Leptin and Adipokine Physiology and is a Clinical Research Overseer at the BIDMC and the Joslin Diabetes Center. In addition, he has a well established track record in mentoring clinical researchers. The candidate's immediate goal is to determine the role leptin and other adipokines play in normal physiology and the pathophysiology of disease states in humans. His long-term goal is to further our understanding of adipokine biology which will eventually lead to new treatments for metabolic syndrome, diabetes, cardiovascular disease, and obesity-associated malignancies. In working towards these goals, the candidate has and will continue to be training and establishing a group of outstanding clinical investigators studying complementary aspects of energy homeostasis and metabolic disorders. A K24 award will enable the applicant to realize these goals by providing more protected time for both patient-oriented research and mentoring. The environment for this research is outstanding with many successful faculty involved in this general area of research across the Harvard Medical System. The PI has access to "state of the art" facilities in the General Clinical Research Center (GCRC) as well as ongoing large cohort studies including the Nurses Health Study and the Health Professionals Study. The indicative research protocols described herein involve the administration of recombinant human leptin in the context of GCRC-based, randomized, placebo-controlled trials, to subjects with hypothalamic amenorrhea or the HIV-associated metabolic syndrome and/or to healthy volunteers to study physiology outcomes, leptin signaling, and/or activation of hypothalamic centers by leptin in humans. Moreover, the PI is presenting some of his studies on the role of adiponectin as the link between obesity, insulin resistance and colon cancer, ranging from large observational cohort studies, to studies of human samples ex vivo, to molecular biology and mechanistic animal studies in the laboratory. The applicant is also actively participating in several other observational cohort studies as well as GCRC-based interventional studies on the treatment of obese diabetic subjects. Human obesity and its associated metabolic disorders are among the largest public health challenges of our time. Understanding the mechanisms underlying these disorders is key to finding safe and effective treatments.